Time Trends of Period Prevalence Rates of Patients with Inhaled Long-Acting Beta-2-Agonists-Containing Prescriptions: A European Comparative Database Study
Time Trends of Period Prevalence Rates of Patients with Inhaled Long-Acting Beta-2- Agonists-Containing Prescriptions: A European Comparative Database Study
Marietta Rottenkolber 0 1 2
Eef Voogd 0 1 2
Liset van Dijk 0 1 2
Paola Primatesta 0 1 2
Claudia Becker 0 1 2
Raymond Schlienger 0 1 2
Mark C. H. de Groot 0 1 2
Yolanda Alvarez 0 1 2
Julie Durand 0 1 2
Jim Slattery 0 1 2
Ana Afonso 0 1 2
Gema Requena 0 1 2
Miguel Gil 0 1 2
Arturo Alvarez 0 1 2
Ulrik Hesse 0 1 2
Roman Gerlach 0 1 2
Joerg Hasford 0 1 2
Rainald Fischer 0 1 2
Olaf H. Klungel 0 1 2
Sven Schmiedl 0 1 2
0 1 Institute for Medical Information Sciences , Biometry, and Epidemiology , Ludwig-Maximilians-Universitaet Muenchen , Munich, Germany , 2 Utrecht Institute for Pharmaceutical Sciences, Division Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, the Netherlands, 3 Netherlands Institute for Health Services Research, Utrecht, the Netherlands, 4 Novartis Pharma AG, Basel, Switzerland, 5 Division Clinical Pharmacy & Epidemiology, University of Basel , Basel, Switzerland, 6 European Medicines Agency, London , United Kingdom , 7 Pharmacology Unit, Department of Biomedical Sciences II, School of Medicine and Health Sciences, University of Alcala , Madrid , Spain , 8 BIFAP Unit, Division of Pharmacoepidemiology and Pharmacovigilance, Spanish Agency for Medicines and Medical Devices , Madrid, Spain, 9 Danish Medicines Agency (Laegemiddelstyrelsen) , Medicines Control Division , Copenhagen , Denmark , 10 National Association of Statutory Health Insurance Physicians of Bavaria , Munich, Germany , 11 Medizinische Klinik und Poliklinik V, University Hospital , Ludwig-Maximilians- Universitaet Muenchen, Munich, Germany , 12 Department of Clinical Pharmacology, School of Medicine, Faculty of Health, Witten/Herdecke University , Witten, Germany , 13 Philipp Klee-Institute for Clinical Pharmacology, HELIOS Clinic Wuppertal , Wuppertal , Germany
1 Funding: The PROTECT project has received support from the Innovative Medicine Initiative Joint Undertaking (www.imi.europa.eu) under Grant Agreement n 115004, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007- 2013) and EFPIA companies' in-kind contribution. In addition, as a special form of the IMI JU grant, Utrecht University and University of Alcala received a
2 Academic Editor: Heiner K. Berthold, Bielefeld Evangelical Hospital , GERMANY
Inhaled, long-acting beta-2-adrenoceptor agonists (LABA) have well-established roles in
asthma and/or COPD treatment. Drug utilisation patterns for LABA have been described,
but few studies have directly compared LABA use in different countries. We aimed to
compare the prevalence of LABA-containing prescriptions in five European countries using a
A common study protocol was applied to seven European healthcare record databases
(Denmark, Germany, Spain, the Netherlands (2), and the UK (2)) to calculate crude and
age- and sex-standardised annual period prevalence rates (PPRs) of LABA-containing
prescriptions from 20022009. Annual PPRs were stratified by sex, age, and indication
(asthma, COPD, asthma and COPD).
direct financial contribution from Pfizer and
AstraZeneca, respectively. The funders had no role in
study design, data collection and analysis, decision to
publish, or preparation of the manuscript. Co-authors
Paola Primatesta and Raymond Schlienger are
employed by Novartis Pharma AG. Novartis Pharma
AG provided support in the form of salaries for
authors PP and RS, but did not have any additional
role in the study design, data collection and analysis,
decision to publish, or preparation of the manuscript.
Competing Interests: Utrecht University and
University of Alcal received a direct financial
contribution from Pfizer and AstraZeneca,
respectively, as a special form of the IMI JU grant.
LVD reports grants from AstraZeneca (outside the
submitted work) and grants from Bristol
MyersSquibb (outside the submitted work); CB reports that
her department at the University of Basel received
payment from Novartis Pharma AG, Basel,
Switzerland, during the conduction of the study for
statistical analyses; MDG reports grants from Top
Institute Pharma (NL), www.tipharma.com; SS reports
personal fees from Rottapharm Madaus (Cologne,
Germany, outside the submitted work); PP and RS
are employed by Novartis belonging to EFPIA
(European Federation of Pharmaceutical Industries
and Association) member companies in the IMI JU,
and costs related to their part in the research were
carried by the respective company as in-kind
contribution under the IMI JU scheme. Co-authors
Paola Primatesta and Raymond Schlienger are
employed by Novartis Pharma AG. Novartis Pharma
AG provided support in the form of salaries for
authors PP and RS, but did not have any additional
role in the study design, data collection and analysis,
decision to publish, or preparation of the manuscript.
There are no patents, products in development or
marketed products to declare. This does not alter the
authors adherence to all the PLOS ONE policies on
sharing data and materials.
From 20022009, age- and sex-standardised PPRs of patients with LABA-containing
medications increased in all databases (58.2%185.1%). Highest PPRs were found in men 80
years old and women 7079 years old. Regarding the three indications, the highest
ageand sex-standardised PPRs in all databases were found in patients with asthma and
COPD but with large inter-country variation. In those with asthma or COPD, lower PPRs
and smaller inter-country variations were found. For all three indications, PPRs for
LABAcontaining prescriptions increased with age.
Using a standardised protocol that allowed direct inter-country comparisons, we found
highest rates of LABA-containing prescriptions in elderly patients and distinct differences in the
increased utilisation of LABA-containing prescriptions within the study period throughout
the five European countries.
Asthma and chronic obstructive pulmonary disease (COPD) are two of the most prevalent
chronic diseases worldwide . Thus, global, evidence-based initiatives were developed to
improve and standardise the treatment of both diseases [2, 3]. Despite the wide acceptance of
these guidelines, frequent off-label use of respiratory drugs has been reported, especially in
children [4, 5]. Long-acting beta-2-agonists (LABA) are a key drug class for the treatment of both
COPD and asthma [2, 3]. After the SMART trial , the risks of LABA use in asthma patients
not receiving inhaled corticosteroids (ICS) were widely discussed . Most recently, several
publications have also reported relevant risks for the combination of LABA and ICS in asthma
patients [8, 9]. In addition, some data have called into question the benefit-risk profile of
LABA in COPD patients .
Despite the broad use of LABA-containing drugs and the unsolved issues regarding risks
and benefits, there are still only a limited number of drug-utilisation studies that provide
detailed data on LABA-containing medications [11, 12]. In particular, carefully conducted,
intercountry comparisons of drug treatment characteristics and of populations at risk of
overtreatment are scarce . Unfortunately, most available studies compare different types of
databases, time periods, etc. limiting the value of these inter-country comparisons to a significant
Our goal was to compare the prevalence of LABA-containing prescriptions in seven
databases from five different European countries that are part of the collaborative effort
known as Pharmacoepidemiological Research on Outcomes of Therapeutics by a European
Consortium (PROTECT) . To the best of our knowledge, this analysis represents the
first study in which the prevalence of LABA-containing prescriptions is optimally
compared across different countries by the application of a standardised protocol.
Furthermore, we specifically stratified the prevalence of the LABA-containing
prescriptions by age, sex, calendar year and recorded indication (asthma, COPD,
asthma and COPD).
The following seven European healthcare record databases were analysed: Mondriaan
Netherlands Primary Care Research Database (Mondriaan-NPCRD, The Netherlands) ,
MondriaanAlmere Health Care Group (Mondriaan-AHC, The Netherlands) , The United
Kingdom Clinical Practice Research Datalink (CPRD, United Kingdom) , The Health
Improvement Network (THIN, United Kingdom) , Computerized Database for
Pharmacoepidemiological Studies in Primary Care (BIFAP, Spain) , The Bavarian Association of
Statutory Health Insurance Physicians database (Bavarian DB, Germany) , and the Danish
national registries (DKMA, Denmark) . The different databases cover regionally / nationally
representative populations of 170,000 to 10.5 million people. The main characteristics of the
databases are presented in Table 1 and have been described in detail elsewhere .
There is some overlap of doctors offices in the UK databases, CPRD and THIN (n = 327 for
CPRD and THIN combined, n = 286 for CPRD alone, and n = 168 for THIN alone) . The
documented data from the overlapping practices were included in the analyses of each
database, and therefore they are not mutually exclusive. There was no overlap between the two
Dutch databases. The International Statistical Classification of Diseases and Related Health
Problems (ICD-10), the International Classification in Primary Care (ICPC) or the Read
Codes were used for coding diagnoses. The Anatomical Therapeutic Chemical classification
system (ATC) or Multilex Codes were used for coding drugs.
Study population and study period
All patients with available data within the period of valid data collection (January 1, 2002
December 31, 2009) were included in this study. In two databases (Bavarian DB and
MondriaanAHC) the study period differed slightly (20042008 and 20022008, respectively).
Since 2008 was the year with the most recent information available in all of the databases, it
was the year selected for the analyses of indication and number of prescriptions per year.
Exposure definition. Exposure was defined as at least one prescription containing an
inhaled long-acting beta-2-adrenoceptor agonist (LABA; salmeterol or formoterol) including
fixed combination drugs (S1 Table) irrespective of any other concomitant medication.
Crude annual period prevalence rates (PPRs) were calculated for all patients with
LABAcontaining prescriptions (irrespective of indication) by dividing all patients with at least one
recorded prescription for a LABA-containing medicine by the total number of people available
in each database at midyear. For all PPRs, direct standardisation by age and sex was performed
based upon the European standard population in 2008 [23, 24]. 95% Confidence intervals
were calculated for crude PPR based on the modified Wald method and for the age-and
sexstandardised PRR according to the Spiegelman method [25, 26].
The PPRs were calculated stratifying by age (ten-year age groups) and sex. For the Bavarian
database, the youngest age group available was 019 years. For the analysis of the annual
number of inhaled LABA-containing prescriptions per patient the following categories were
used: 1 prescription, 211 prescriptions, 1223 prescriptions, 24+ prescriptions.
Stratification by indication was performed for the year 2008 for all patients receiving at least one
LABA-containing prescription. The indication was defined retrospectively at the date of the
last LABA prescription within the study period (20022009). This entailed searching the entire
study period backwards for medical codes to classify the patients into the following mutually
C K R TH Im B D P S D re
exclusive categories: asthma, COPD, asthma and COPD, and other and unknown.
Asthma and COPD were defined by ICD-10, ICPC or Read codes (S2S5 Tables). The category
other and unknown includes patients with a diagnosis other than asthma or COPD or not
having a documented diagnosis. In the DKMA database, the stratification by indication was
not performed. Additional crude and standardised annual PPRs were calculated for the strata
asthma, COPD and asthma and COPD for each year in the study period. The
denominator for these analyses was the number of patients who were available in the respective stratum
of each database at midyear. Comparing groups, the chi-square test was used for categorical
variables. P-values <0.05 were considered statistically significant.
I. All patients with LABA-containing prescriptions (irrespective of
Annual period prevalence rates. The age- and sex-standardised annual PPRs of patients with
LABA-containing prescriptions increased for all databases from 2002 onwards (Fig. 1a). The
highest percentage increase within the study period was observed in the BIFAP and the CPRD
database at 185.1% and 116.3%, respectively. The lowest increase was found in the
MondriaanNPCRD database at 58.2%.
In 2008, the MondriaanAHC database and the BIFAP database had the highest
standardised PPR (4.4 per 100 persons and 4.0 per 100 persons, respectively). The lowest standardised
PPRs in 2008 were observed in the Bavarian DB and MondriaanNPCRD databases (2.8 per
100 persons and 2.9 per 100 persons, respectively) (Table 2).
The PPR of the Mondriaan-AHC database was most affected by the standardisation
procedure (3.6 per 100 persons before standardisation, 4.4 per 100 persons after standardisation).
Only minor changes were detected in the other databases after standardisation.
Annual period prevalence rates stratified by age and sex. Table 3 shows the results for the
sex-specific PPRs of patients with LABA-containing prescriptions, stratified by age, for the
year 2008. The same patterns were observed in all other years (data not shown). The PPR was
higher in men, particularly in males 020 years old and males over 70 years old. A continuous
increase over the age groups was observed for females until the age of 80 years. For females
80 years old, a decrease in PPR was noted. The situation was different for males, as their PPR
3.5 (3.53.5) 3.6 (3.53.6) 4.4 (4.34.6)
4.0 (3.94.0) 2.8 (2.82.8) 3.0
Persons with at least one
Total number of persons in
the database at mid-year
Crude annual PPR per 100
persons (95% CI)
Standardised annual PPR
per 100 persons (95% CI)
LABA: Long-acting beta-2-agonist.
n.a.: not available.
PPR: Period prevalence rate.
CI: Confidence interval.
2,706 (52.5%) 3,529 (39.4%)
12,619 (8.9%) 16,428 (5.1%)
4,515 (3.5%) 5,963 (3.9%) 1,327 (25.7%) 1,939 (21.6%)
3.5 (2.94.1) 3.6 (3.14.2) 3.6 (1.48.4)
3.9 (3.05.0) 2.9 (2.04.1) 2.9
9.4 (9.39.5) n.a.
PPR respon lae .6 ..()0023 .20 ..)0942 .21 ..()3034 .16 ..()0636 .19 ..()0939 .28 ..()1552 .44 ..()2673 .81 ..(47134 .80 ..(35164 .26 ..()2133
M 0 (
.)03 .)35 .)39 .)52 .)68 .)75 .)71 .)34
.)03 .)33 .)33 .)25 .)0114 .4 ..1480 7 ..2322 .)45
it-acnnoA CHA 010 I)5C% leaem .5 ..)(84300 .22 ..)43500 .22 ..)(63300 .27 ..)(23300 .48 ..)(23400 .64 ..)(04800 .86 ..)(75500 .119 ..)(07300 .100 ..()97300 .42 ..()21109
)foLPRAB iraaondnM repPPR (ress9pon leaF .91 ..()00342 .26 ..)(00334 .31 ..()00360 .18 ..()00334 .26 ..()00303 .44 ..()00374 .61 ..()00554 .911 ..()00743 .112 ..()00857 .31 ..()03108
P M 1 (
PPR rseonp lea .8 ..)(2300 .22 ..)9490 .71 ..)(3450 .22 ..)(9409 .26 ..)(2513 .35 ..)(5618 .58 ..)(6934 .86 ..(14450 .94 ..(18442 .34 ..()4227
continued to increase and was highest in the age group 80 years. In the BIFAP database,
the highest PPR was observed among males aged 80 years, at 16.7 per 100 persons.
Number of LABA prescriptions in 2008. The number of LABA-containing prescriptions
per year was significantly different between the database (p<0.0001). In all databases most
patients received 211 LABA-containing prescriptions per year (between 52.2% and 75.8%). The
proportion of patients with only one annual prescription was much higher in the BIFAP and
Bavarian DB (34.7% and 29.2%) compared to the UK databases CPRD (14.1%) and THIN
(14.5%) (Fig. 2a).
Analysis of indication. As shown in Table 2 for the 2008 data, significant differences were
observed among the databases regarding the documented indications for the prescribing of a
LABA-containing medication (p<0.0001). In all databases most patients were coded as
asthma patients [without a COPD diagnosis] (between 36.2% and 52.2%). The proportion of
COPD [without an asthma diagnosis] patients varied between 10.2% and 22.9%. Between 3.2%
(MondriaanAHC) and 34.1% (Bavarian DB) of all patients receiving LABA-containing
prescriptions were coded as having both asthma and COPD. The number of patients with
other and unknown diagnoses was lowest in the UK databases (3.5% (THIN), 3.9% (CPRD))
and highest in the BIFAP database (27.6%).
II. Stratification of results according to the three main indications
Annual period prevalence rates. With respect to the three patient strata (asthma, COPD,
and asthma and COPD), the highest age- and sex-standardised PPR of patients with
LABA-containing prescriptions was observed in the asthma and COPD stratum in all
databases and all years (Fig. 1 b-d, details for 2008 are in Table 2). An increase in age- and
sexstandardised PPR was observed in all three strata and all databases from 2002 onwards;
however, the extent of the increase was different. In the asthma stratum, the PPR of the last year of
the study period was between 1.72.0 times higher than in the first year of the study period; for
the COPD stratum the PPR increased by 1.52.4 times in BIFAP and the two Dutch
databases and by 6.2 and 7.6 times in the THIN and CPRD database.
Number of LABA-containing prescriptions in 2008. In all databases and in all three strata,
most patients received 211 prescriptions per year. In all databases, the highest proportion of
patients who received only 1 annual LABA-containing prescriptions was found in the asthma
stratum whereas lowest proportion was found in the stratum asthma and COPD (Fig. 2 b-d).
By analysing seven databases from the electronic health records of five European countries
with a standardised protocol, we found an increase in the prescribing of LABA-containing
medications during the course of the study period. This increase was found in all patients with
LABA-containing prescriptions as well as in patients diagnosed with asthma and, most notably,
with COPD. During the study period, there were changes in asthma and COPD treatment
guidelines, changes in the approved indications for using combined, fixed-dose ICS plus LABA
products in COPD, and a regulatory warning issued regarding LABA use without ICS in
asthma patients. These issues may have contributed to the changes over time found in our study
and by others .
Despite the similar temporal trend in all databases, relevant inter-country differences in the
prescribing prevalence rates for LABA-containing medications were discovered in our study.
The differences among the databases were not reduced after standardising our results to the
European reference population . Thus, sex- and age-independent differences in LABA
prescribing behaviour were confirmed among the five countries.
The TEDDY study, a pediatric asthma study, is one of the few studies that has examined
LABA prescribing patterns by performing inter-country (Netherlands, Italy, and the UK)
comparisons . These investigators found results similar to ours, but there were methodological
differences worth mentioning and limiting comparability. For example, in our study children
were represented only by two age groups and we found in all databases higher PPRs of patients
with LABA-containing prescriptions in children aged 1019 years compared to 09 years. In
the TEDDY study, an age-related increase was reported for LABA-ICS (fixed combination) for
different age groups whereas data for LABA (regardless of ICS use) were not reported in detail
. Other indirect comparisons using national data  are of limited value due to different
study periods and different data sources.
In our study, large differences were found between the two Dutch databases. The
Mondriaan-AHC population is somewhat younger than the Mondriaan-NPCRD population.
However, even after standardisation for age and sex, we still observed a higher rate of prescribing
LABA-containing medications in Mondriaan-AHC as compared to Mondriaan-NPCRD. The
main difference between the two databases is that Mondriaan-AHC also includes pharmacy
medication dispensings from other specialties than GP in addition to GP prescriptions,
whereas Mondriaan-NPCRD only covers GP prescriptions. Results for the two UK databases (CPRD
and THIN) are more comparable due to the large overlap of the included practices (n = 327,
resembling > 50%), and potentially due to the introduction of the Quality and Outcomes
Framework, with its specifications regarding data collection and monitoring for asthma and COPD,
during the study period .
Our inter-country analyses revealed a difference in the proportions of the main indications
(asthma and/or COPD) for LABA-containing prescriptions. We found that patients diagnosed
with asthma (asthma and asthma and COPD) accounted for 49.8% to 86.0% of patients
prescribed a LABA-containing medication. A study out of the UK found that 76% of patients
receiving a short- or long-acting bronchodilator had at least a diagnosis of asthma .
Nevertheless, the comparability of this prior study to our study is limited due to (1) the combined
analysis of SABA (salbutamol, terbutalin and fenoterol) and the LABA compound salmeterol
and (2) changes in prescribing habits over time since the patients in the UK study were
included before 1994 and several changes to treatment guidelines have been made in the interval
between the two study periods. Nevertheless, the predominance of diagnosed asthma, with and
without concomitant COPD, in patients treated with LABA in the UK is indirectly confirmed
in our study by a higher prevalence rate of asthma compared to the other countries. Indeed, in
the UK and the Netherlands, the prevalence rates for clinical asthma were recently reported
to be 18.2% and 15.3%, respectively, whereas lower values were reported for Denmark (10.2%),
Germany (7.6%), and Spain (7.1%) .
An age-specific analysis of overall LABA prescribing is influenced by the age-specific
prevalence rates of asthma and COPD. Consistent with this, we found two prevalence peaks (in
children and in elderly patients) that were previously reported for bronchodilators (including
SABA compounds) . In our study, variations among the PPRs for LABA-containing
medications in the different databases were less pronounced in younger patients compared to
elderly patients. This may be attributable to pronounced differences in consultation patterns, as well
as in prevalence rates of respiratory diseases in elderly patients between the countries included
in our analysis. In addition to inter-country differences, intra-country differences as observed
in other studies  may also have some influence on our results.
In two databases (BIFAP, Mondriaan-AHC), approximately one quarter of all patients
receiving LABA-containing medication had neither a recorded diagnosis of asthma nor of
COPD during the study period. One can hypothesize that these patients receiving
LABAcontaining drugs had a diagnosis of asthma or COPD recorded before the study period or
that they were diagnosed with an acute bronchitis, which is not a labelled indication for LABA
(i.e., off-label use). In future studies, these potential explanations should be examined in
According to the global initiatives for asthma and COPD and national guidelines of the
countries included in this study, LABA-containing medication is recommended as controller
medication [2, 3]. Nevertheless, the number of LABA-containing prescriptions per patient
differed in our study to some extent between the countries and e.g. up to 30% of all asthma
patients with a LABA-containing prescription received only one prescription. As shown in
several studies, poor medication persistence with controller/maintenance drugs is an important
issue in the long-term treatment of asthma and COPD [30, 31]. On the other hand, a small
number of prescriptions might also be the result of other factors such as the more frequent
reassessment of patients symptoms in terms of high-quality guideline adherence. With respect
to the initiation of LABA treatment, good guideline adherence has been confirmed in the UK
. Furthermore, variations in package size of LABA-containing medications between the
countries might also contribute to the differences shown in our study.
In addition to the limitations stated above there are points which may have impacted this
study. First, we estimated PPRs of patients with LABA-containing prescriptions irrespective of
any other comedications (e.g. ICS) and clinical conditions (e.g. lung function parameters).
Therefore, no statements regarding guideline adherence with respect to disease severity or
combined drug therapy (e.g. concomitant use of LABA and ICS in asthma patients) can be
made. In addition, by using drug prescription data (and not primarily indication data) for
calculating PPRs, we were not able to calculate exact disease prevalence rates for asthma or COPD
due to the non-inclusion of untreated persons or persons receiving other respiratory
medications. Nevertheless, it has been shown that respiratory drug utilisation is a sufficient proxy for
estimating disease prevalence rates . Hence, estimation of disease prevalence rates by using
LABA-containing prescription data might focus on patients diagnosed with more severe
asthma and / or COPD. Second, we included data from the ambulatory sector only and thus other
settings, such as hospitals, are not covered by our study. Third, since in most of the databases
used in our study no direct linkage between drug prescription and indication is documented,
all indications documented within the entire study period were used (static assessment of
indication). Thus, a patient diagnosed with asthma first who later developed COPD was grouped
into the asthma and COPD stratum. Since a significant number of (elderly) patients are
suffering from both diseases, asthma and COPD (Asthma-chronic obstructive pulmonary disease
overlap syndrome (ACOS)) [34, 35] a combined stratum asthma and COPD is justified.
Furthermore, asthma and COPD are chronic diseases in most adults making a static
assessment meaningful from a medical point of view. Nevertheless, over- as well as underestimation
of indications influencing our study results cannot be ruled out. Fourth, there are uncertainties
in the diagnosing of asthma and/or COPD under real life conditions that can result in
misclassifications [36, 37]. Due to feasibility reasons and the primarily methodological character of
our study, we abstained from validating documented indications but in all databases, regular
routine data quality checks are performed. Fifth, non-COPD (acute) bronchitis, has a high
prevalence rate in the young and in the elderly  and might be miscoded and registered as
asthma in younger patients and as COPD in the elderly possibly influencing the results of our
study. Sixth, since databases from different countries were included in our study, coding
systems of diseases and drugs differs significantly. Despite a comprehensive and detailed mapping
process, diagnoses and diseases might differ to some extent beyond the coding dictionaries we
used to map them. Seventh, type of data (prescription data) and exclusion of prescriptions
made by specialists were comparable for most databases. Nevertheless, for a few databases only
dispensing data and data including prescriptions by specialists could be used influencing our
study results. To sum up, the databases included in our study differ in several aspects. From a
methodological point of view, this issue has been the main topic of interest in terms of how to
overcome these differences. Nevertheless, several aspects mentioned above could not be fully
addressed in this study and will limit the comparability of our results to some extent. In our
study, comparability of results was improved by age- and sex standardisation of PPRs
according to the European reference population and by using a standardised protocol.
For the first time, we directly compared prescription data regarding LABA-containing drugs
during the time period of 20022009 using seven databases from five Western European
countries. Following a standardised protocol, we found an increasing trend for the period prevalence
rate of patients with LABA-containing prescriptions in all five countries, and this was most
pronounced in patients diagnosed with COPD even after age- and sex-standardisation. Despite
some similarities in the PPRs of patients with LABA-containing prescriptions across countries,
we uncovered several inter-country differences (e.g. number of prescriptions per patient in
12 months, prescription pattern in elderly patients). From a methodological perspective, we
did confirm that our approach was a feasible tool for inter-country analyses of drug
prescription data reflecting real-life conditions. Due to the standardized protocol, additional
countries could be included in future studies.
We thank Arlene Gallagher (Clinical Practice Research Datalink, London, United Kingdom),
Xavier Kurz (European Medicines Agency, London, United Kingdom), Omer de Mol
(Genzyme Europe B.V., The Netherlands), Saga Johanson (AstraZeneca AB, Sweden), Frans Rutten
(Utrecht University, Utrecht, The Netherlands), Kourtney Davis (GlaxoSmithKline Research
and Development LTD, Belgium) for reviewing the study protocol. We thank Kourtney Davis
(GlaxoSmithKline Research and Development LTD, Belgium), Petra Thrmann (Department
of Clinical Pharmacology, Witten/Herdecke University, Germany; Philipp Klee-Institute for
Clinical Pharmacology, HELIOS Clinic Wuppertal, Germany), Estel Plana (Novartis
Farmaceutica S.A., Barcelona, Spain), Consuelo Huerta (BIFAP Unit, Division of
Pharmacoepidemiology and Pharmacovigilance, Spanish Agency for Medicines and Medical Devices, Madrid,
Spain), Francisco de Abajo (Pharmacology Unit, Department of Biomedical Sciences II, School
of Medicine and Health Sciences, University of Alcal, Madrid, Spain; Clinical Pharmacology
Unit, University Hospital Prncipe de Asturias, Madrid, Spain), and Robert Reynolds
(Epidemiology, Pfizer, New York, NY, USA) for their valuable comments to this manuscript. We
would also like to express our gratitude to Elizabeth Costello for language check.
The authors would like to thank the excellent collaboration of the physicians in the
participating countries, who used high standards while recording their professional practices and
thus made possible the availability of the databases used in this research.
The research leading to these results was conducted as part of the PROTECT consortium
(Pharmacoepidemiological Research on Outcomes of Therapeutics by a European
ConsorTium, www.imi-protect.eu/) which is a public-private partnership coordinated by the
European Medicines Agency. The views expressed in this article are the personal views of the authors
and may not be understood or quoted as being made on behalf of or reflecting the position of
the European Medicines Agency or one of its committees or working parties.
Conceived and designed the experiments: MR SS EV CB PP RF YA JS JD RS LVD OHK MDG
A. Afonso GR A. Alvarez MG UH JH RG. Wrote the paper: MR SS EV CB PP RF YA JS JD RS
LVD OHK MDG A. Afonso GR A. Alvarez MG UH JH RG. Analyzed the data, THIN database:
YA JS JD. Analyzed the data, CPRD database: CB PP RS. Analyzed the data, Mondriaan
database: EV LVD OHK MDG. Analyzed the data, Bifap database: A. Afonso GR A. Alvarez MG.
Analyzed the data, DKMA database: UH. Analyzed the data, Bavarian database: MR SS RG JH
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